ABSTRACT The research projects proposed in this SPORE address genomic instability in breast cancer. Three areas are the focus of study: homologous recombination deficiency, chromosomal instability and APOBEC mutagenesis. Our ultimate plan is to exploit tumor specific vulnerabilities by virtue of their underlying genomic instability. These profiles of genomic instability have offered novel insights about the drivers breast cancer development and progression. There are opportunities for therapeutic advances in breast cancer, which have emerged based on the initial successes, for example, in utilizing homologous recombination deficiency by treatment with a PARP inhibitor. The plan is to determine the optimal use of these agents and develop novel agents for these tumors. Chromosomal instability, which does not necessarily have a unique pattern of mutations, is associated with a poor prognosis, but no specific therapeutic strategy at present. The link between chromosomal instability and innate immune signaling has been made, and the goal is to exploit this connection for therapy. For APOBEC, we know that a characteristic pattern of SNVs are observed, but in this application, we are highlighting the role of APOBEC in the acquisition of drug resistance, and introducing novel approaches for reliably identifying and therapeutically targeting breast cancers with an active APOBEC mutagenesis process. In summary, the goals are to take the risks of genomic instability (poor prognosis, rapid development of resistance) and turn genomic instability into an advantage for therapeutic targeting, thereby improving the prognosis for high risk breast cancers.